Work

A clinically translatable 2.5D lung adenocarcinoma organoid platform derived from malignant pleural effusions for precision drug screening and tumor-immune-stromal modeling

Year: 2025

Type: article

Abstract: Conventional three-dimensional (3D) organoid models are limited by high cost, technical complexity, and poor replication of tumor–immune interactions. To address these limitations, we developed two novel 2.5D systems from malignant pleural effusion (MPE) of patients with lung adenocarcinoma. The first uses MPE-derived adherent cells to create matrix-free niches, while the second combines MPE supernatant with DMEM-F12 and 10–30 % fetal bovine serum, with or without agarose, to form a thermoresponsive matrix that mimics dynamic tumor microenvironments. Autologous MPE supernatants were used to preserve native cytokines and extracellular matrix components. Genomic and immune microenvironment analyses demonstrated over 90 % concordance between 2.5D organoids and parental tumors, which aligned with the standards reported for existing 3D tumor–organoid cultures. The 2.5D organoids retained key functional characteristics, including mucus secretion, phenotypic plasticity, and angiogenesis. Organoid-based high-throughput screening enabled identification of candidate therapeutics, and drug sensitivity assays correlated strongly with patient outcomes, underscoring their utility for personalized medicine. The matrix-free design facilitated rapid organoid generation (3–10 days) and reduced costs by approximately 90 % relative to conventional 3D methods. These 2.5D models provide a clinically translatable platform that replicates tumor heterogeneity while overcoming cost and technical barriers, offering a promising tool for precision pharmacology and oncology. • 2.5D organoids generated from malignant pleural effusions of lung adenocarcinoma. • Matrix-free, cost-effective culture reduces expenses by ∼90 % vs. 3D organoids. • 90 % genomic and immune concordance with parental tumors demonstrated. • Organoids reproduce tumor–immune–stromal interactions and angiogenesis. • Drug response in 2.5D organoids correlates strongly with patient outcomes.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118712